Different effects of telithromycin on MUC5AC production induced by human neutrophil peptide-1 or lipopolysaccharide in NCI-H292 cells compared with azithromycin and clarithromycin.
OBJECTIVE
Mucus hypersecretion is a prominent feature in patients with chronic respiratory tract infections such as cystic fibrosis and diffuse panbronchiolitis, and the clinical effectiveness of macrolide antibiotics has been reported in these patients. Because human neutrophil peptide-1 (HNP-1), an antimicrobial peptide in neutrophils, exists in high concentrations in the airway fluid of these patients, we examined the direct effect of HNP-1 on MUC5AC mucin production using NCI-H292 cells. The effects of macrolide antibiotics on the response were also examined.


METHODS
MUC5AC synthesis was assayed using RT-PCR and ELISA. Phosphorylation of ERK1/2 was determined by western blotting.


RESULTS
Stimulation with HNP-1 or lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa increases the production of MUC5AC mRNA and protein, and an additive effect was found upon co-stimulation with both HNP-1 and LPS. Azithromycin and clarithromycin had inhibitory effects on overproduction of MUC5AC induced by HNP-1 or LPS stimulation. Telithromycin also had an inhibitory effect on MUC5AC production induced by LPS, but not on production by HNP-1. Phosphorylation of ERK1/2 was induced by HNP-1 or LPS stimulation, and azithromycin, clarithromycin and telithromycin had inhibitory effects on ERK1/2 phosphorylation induced by LPS, but not by HNP-1.


CONCLUSIONS
These findings suggest that neutrophil-derived defensins as bacterial components contribute to excessive mucus production in patients with respiratory tract infections, and that macrolide and ketolide antibiotics directly inhibit these actions by interfering with intracellular signal transduction. However, the mechanism of telithromycin inhibition of MUC5AC synthesis may differ from the response induced by azithromycin and clarithromycin.
Ishimoto
Hiroshi
H
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
Mukae
Hiroshi
H
Sakamoto
Noriho
N
Amenomori
Misato
M
Kitazaki
Takeshi
T
Imamura
Yoshifumi
Y
Fujita
Hanako
H
Ishii
Hiroshi
H
Nakayama
Seiko
S
Yanagihara
Katsunori
K
Kohno
Shigeru
S
D000900:Anti-Bacterial Agents / Q000378:metabolism*; D017963:Azithromycin / Q000378:metabolism*; D002460:Cell Line; D017291:Clarithromycin / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D048628:Ketolides / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D055271:Mucin 5AC / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023084:alpha-Defensins / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D048628:Ketolides; D008070:Lipopolysaccharides; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C082161:lipopolysaccharide A; D017963:Azithromycin; D048052:Mitogen-Activated Protein Kinase 3; D017291:Clarithromycin; C106791:telithromycin